Saint Mazie is a historical novel employing techniques traditional to oral storytelling. A present-day documentarian acquires a 90-year-old diary, and is absorbed by the life of Mazie Phillips-Gordon—Jazz Age party girl, ticket-taker, and champion to addicts and bums on New York City's Lower East Side. Mazie's seeming fearlessness and zest are haunted by childhood abuse, and when the Great Depression surges through the Bowery like a black wave, she welcomes anguished friends and strangers—many homeless—into the Venice Theater's comforting fantasies. Despite frequent back-room boozing and romantic flings, Mazie becomes a "saint" to the suffering locals, chronicling in her secret diary hope, horror, and adventure. These entries are accompanied by interviews with people who either knew Mazie, or became fascinated after hearing accounts of her bawdy, spirited life, and of her openhearted support of the Bowery's downtrodden.

Mazie Phillips and sisters Rosie and Jeanie lead a troubled life in pre-World War One Boston. Horvath, their father, is a violent wife-beater; mother Ada cares for her children and is succumbing to abuse. Rosie moves to New York City, and several years later returns with husband Louis to take away her sisters. The unlikely new family lives in a small, but mostly happy, apartment. For her tenth birthday, Mazie is gifted with a brown leather diary, and slowly begins the secret chronicles of her life. Rebellious and willful, Mazie fights off bullies, plays with young sister Jeanie, and spares no one—including herself—from brutally honest treatment in her journal. After a few years, Mazie works in her brother-in-law Louis's ("the Quiet Giant") candy shop, loathes it, and discovers what becomes a life-long love for the streets and their often destitute denizens.

Nearing 20, Mazie meets two sailors, and has a fling with one while the other watches. She drinks nightly, and older sister Rosie warns her against carousing and pregnancy. In a dusty gypsy parlor, the sisters have their fortunes told, and Mazie realizes Rosie is trying (and failing) to have a baby with Louis. A gypsy potion, and depression, sicken Rosie; Louis demands Mazie take over her sister's ticket-tearing job at his theater: the Venice. This is also his way of keeping an eye on Mazie, and protecting her from her wildness.

Mazie declares the ticket booth a cage—she'll miss out on life and die there. Instead, she masters the 12-hour days and thrives, meeting Nance (a ragged addict), whose starving children spark Mazie's passion to help the Bowery's bums and homeless. Saddled with a job, Mazie no longer visits the race track, but Jeanie does, meeting a horse doctor: Ethan Fallow. A young nun, Sister Tee, castigates Mazie's drinking on the job, and they somehow become friends. Mazie gets the nun to intervene on behalf of Nance's malnourished Marie and Rufus, but Marie dies and Nance is arrested. Mazie despairs. News of her mother being gravely ill with a bleeding brain sends Rosie (Mazie is refused) to Boston. In a bar, Mazie meets Captain Benjamin Hazzard, and begins a decades-long sexual tryst. Mazie learns that movie-watching nauseates her, and manager Rudy Wallach hints at morning sickness or "something." Mazie is pregnant from Hazzard, and Rosie asks if she and Louis can have the infant—Mazie agrees, but loses the baby.

The war ends to parades and home-coming soldiers. Absurdly, Prohibition is passed, to little effect. Despairing over her loss, Mazie drinks heavily. Jeanie begs to join fellow street-dancer Belle Barker, a Thalia Theater headliner, but Rosie is against this. Louis plans on moving the family to Coney Island, telling Jeanie she can work his newly purchased bumper cars. Hazzard returns for more, but Mazie says nothing about losing their baby—she's powerless against his charm. Jeanie vanishes, but Mazie knows where she's gone. Six months later, living in Coney Island, Mazie laments over losing the diary— then finds it in Rosie's closet. Louis must now drive Mazie to work, and she hates the loss of freedom. Jeanie, at last, writes from Cleveland where the dance/acrobatics group is selling out shows. Mazie teases Sister Tee about Prohibition halting the soul-saving business. Ada Phillips dies, and Rosie takes a trunk to Boston and gathers her mother's pitiful belongings, including a diary Mazie seizes. This proves an unreadable mess of broken English. Mazie wanted only to know whether she and Jeanie, after "escaping," had been missed.

Rosie compulsively cleans the kitchen. Police shut down Finny's speakeasy, where Mazie drinks, and overhears old neighbor Al Flicker accused of being an anarchist. Louis starts using the ticket booth's safe to stash bags of money, and Mazie wonders if he's a criminal. Jeanie writes from Chicago. A Wall Street building is bombed; Mazie and Sister Tee save a man's bleeding leg. Hazzard visits, and Mazie wishes they could be a normal couple. Rosie's obsessive cleaning escalates, and when Mazie tries to stop her she is slapped away. Jeanie shows up in a Rolls-Royce, her leg in a cast. Mazie suggests Jeanie write of her time with the dance group, and she does, describing catching a venereal disease and spreading it through the other performers. When she broke her leg on stage, they asked her to leave. Mazie does nothing but work, pinches money from Louis's sacks for Sister Tee's homeless bums. Hazzard's Valentine card arrives late, but Mazie hangs it in the booth with those from Jeanie. A drunken date with policeman Mack Walters ends badly for Mazie, and Mack says the cops suspect Al Flicker planted the Morgan building bomb. Ethan courts Jeanie again who, weeks later, disappears. Finally she writes: "I'm not done yet." Mazie, now 24, feels 100, and Louis adopts her: she becomes Mazie Phillips-Gordon. Louis signs over the Venice Theater to her; she practically lives there and runs it, so why not? Captain Hazzard proposes, and Mazie declines. In the morning, Hazzard seems relieved. Mazie returns home to find Rosie sobbing, who thought Mazie abandoned her just like Jeanie did. Six weeks later, Louis dies from a heart seizure, and Rosie begins stealing money-stuffed envelopes given to Mazie from Louis old "business" partners. Jeanie writes from Los Angeles. Mazie gives the money to fund a church charity in her mother's name, and Rosie explodes—leaving the house for a long time. Mazie learns Rosie is collecting rent money from properties once owned by Louis, so she decides to give all the money envelopes to a church, establishing a fund in her mother's name and managed by Sister Tee.

Mazie one night finds now-gray Rosie sleeping on the couch and decides to forgive her; if only Rosie can forgive herself. Later, Mazie pulls Rosie from the freezing ocean and they hug, Mazie promising never to abandon her crazy sister. They move back into the city, very close to Louis's original house on Grand Street. Rosie's shouting bothers the neighbors, and it seems she cannot bear any address for longer than six months.

Mack Walters dies. At the boozing cop's funeral, Mazie wonders if any of Mack's pals had a hand in beating Al Flicker. Mazie tells Captain Hazzard they will be friends and nothing more. Sister Tee invites Mazie up to her tiny room, and they embrace in her bed, but not in a sexual manner (though Mazie senses erotic attraction). Tee then vanishes for six weeks, and when they meet again Mazie sees how ill her dear friend appears. Tee later dies from breast cancer, and Mazie tells Hazzard about Tee, losing the baby, everything. Hazzard weeps. Mazie evolves, and buys twelve beds for the homeless, and other items. Grown-up Rufus (Nance's surviving child) who Mazie helped get an apple-picking job, sends a crate of them to the booth. Mazie hands them out, reserving but one for herself. Mazie walks in on Al Flicker (now possibly brain-damaged from police beatings) with Rosie in his lap. They are in love.

Mazie gets pregnant after a night with Al's nephew George, and apparently (this isn't revealed) doesn't have the baby. A five-year gap in Mazie's journaling, and she comes back vowing to devote what's left of her life to serving the downtrodden of New York City. It cannot be forgotten that someone once loved them, and Mazie is their champion: Saint Mazie, queen of the Bowery.